Azacycloalkanone serine protease inhibitors

Abstract

The present invention is directed to non-peptidic factor Xa inhibitors which are useful for the treatment of arterial and venous thrombotic occlusive disorders, inflammation, cancer, and neurodegenerative diseases. The factor Xa inhibitors provide compounds having Formula I: or pharmaceutically acceptable salts thereof; wherein Q is phenyl, benzyl, pyridyl, thienyl, indolyl, quinolinyl, benzothienyl, biphenylyl, or imidazolyl; any of which can include one or more optional substituents independently selected from halo, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1 alkoxy, C 1-3 alkyl, methylenedioxy, carboxamido, acetamido, or amidino; X is methylene, carbonyl, or sulfonyl; Z is methylene, ethylene, or propylene; M is methylene or ethylene; and R 1 R 2 and R 3 are independently hydrogen or C 1-3 alkyl.

1. A compound having Formula I: 
                 
 
       or pharmaceutically acceptable salts thereof; wherein
 Q is C 6-14  aryl, C 6-14  ar(C 1-4 )alkyl, C 6-14  ar(C 2-4 )alkenyl, pyridyl, thienyl, indolyl, quinolinyl, benzothienyl, or imidazolyl; any of which can include one or more optional substituents independently selected from halo, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1-3  alkoxy, C 1-3  alkyl, methylenedioxy, carboxyamino, C 1-4  alkoxycarbonylamino, C 6-10  aryloxycarbonylamino, C 7-11  aralkoxycarbonylamino, aminocarbonyl, mono- or di-(C 1-4 )alkylaminocarbonyl, acetamido, amidino, pyridyl, naphthyl, pyrimidinyl, alkenyl, mono- or di- (C 1-4 )alkylamino, or combinations thereof;  
 X is methylene, carbonyl, or sulfonyl;  
 R 1  is hydrogen or C 1-3  alkyl;  
 n is 1;  
 m is 1-4;  
 R 2  is hydrogen or C 1-3  alkyl;  
 R 3  is hydrogen or C 1-3  alkyl; and  
 R 4 , R 5  and R 6  are independently hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, cyano or —CO 2 R W , where R W  is C 1-4  alkyl, C 4-7  cycloalkyl, benzyl, 
                 
 
 R d , R e  and R g  are each hydrogen, R f  is methyl, and R h  is benzyl or tert-butyl.  
 
     
     
       2. The compound of  claim 1 , wherein Q is C 6-14  aryl, C 6-14  ar(C 1-4 alkyl, C 6-14  ar(C 2-4 )alkenyl, or thienyl, any of which can include one or more optional substituents independently selected from the group consisting of halo, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1-3  alkoxy, C 1-3  alkyl, methylenedioxy, carboxyamino, C 1-4  alkoxycarbonylamino, C 6-10  aryloxycarbonylamino, C 7-11  aralkoxycarbonylamino, aminocarbonyl, mono- or di- (C 1-4 )alkylaminocarbonyl, acetamido, amidino, pyridyl, naphthyl, pyrimidinyl, alkenyl, mono- or di-(C 1-4 )alkylamino, and combinations thereof. 
     
     
       3. The compound of  claim 2 , wherein Q is phenyl or biphenyl, any of which can include one or more optional substituents independently selected from the group consisting of halo, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1-3  alkoxy, C 1-3  alkyl, methylenedioxy, carboxyamino, C 1-4  alkoxycarbonylamino, C 6-10  aryloxycarbonylamino, C 7-11 aralkoxycarbonylamino, aminocarbonyl, mono- or di- (C 1-4 )alkylaminocarbonyl, acetamido, amidino, pyridyl, naphthyl, pyrimidinyl, alkenyl, mono- or di- (C 1-4 )alkylamino, and combinations thereof. 
     
     
       4. The compound of  claim 2 , wherein Q is 4-(2-methylphenyl)phenyl, 4-(2-methoxyphenyl)phenyl, 4-(3-chlorophenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(3-methoxyphenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(4-methylphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 4-(2,4-difluorophenyl)phenyl, 4-(3,4-dichlorophenyl)phenyl, 4-(3,4-dimethoxyphenyl)phenyl, 4-naphth-2-ylphenyl, 4-pyrid-4-ylphenyl, 4-pyrid-2-ylphenyl, biphenyl, 4-(4-chlorophenyl)phenyl, 4-pyrimidin-5-ylphenyl, or 5-(pyrid-5-yl)thien-2-yl. 
     
     
       5. The compound of  claim 4 , wherein X is SO 2 . 
     
     
       6. The compound of  claim 1 , where R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and isopropyl. 
     
     
       7. The compound of  claim 1 , where R 1 , R 2 , and R 3  are hydrogen. 
     
     
       8. The compound of  claim 1 , where R 4 , R 5 , and R 6  are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl hydroxy, methoxy, ethoxy, cyano, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , and —CO 2 CH 2 CH 2 CH 3   
     
     
       9. The compound of  claim 1 , where R 4 , R 5  and R 6  are each hydrogen. 
     
     
       10. The compound of  claim 1 , wherein m is 1 or 2. 
     
     
       11. The compound of  claim 1 , wherein R W  is C 1-4  alkyl, C 4-7  cycloalkyl, or benzyl. 
     
     
       12. The compound of  claim 1 , wherein Q is 4-ethenylphenyl. 
     
     
       13. The compound of  claim 1 , wherein:
 Q is phenyl, biphenyl, naphthyl, benzyl, phenethyl, naphthylmethyl, or thienyl, any of these groups being optionally substituted by one to three optional substituents independently selected from halo, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1-3  alkoxy, C 1-3  alkyl, methylenedioxy, carboxyamino, C 1-4  alkoxycarbonylamino, C 6-10  aryloxycarbonylamino, C 7-11 aralkoxycarbonylamino, aminocarbonyl, mono- or di-(C 1-4 )alkylaminocarbonyl, acetamido, amidino, pyridyl, naphthyl, pyrimidinyl, alkenyl, mono- or di- (C 1-4 )alkylamino;  
 X is carbonyl or sulfonyl;  
 n is 1;  
 m is 1 or 2;  
 R 1 , R 2  and R 3  are hydrogen; and  
 R 4 , R 5  and R 6  are independently hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, cyano or —CO 2 R W , R W  is C 1-4 alkyl, C 4-7 cycloalkyl, benzyl, 
                 
 
 R d , R e  and R g  are each hydrogen, R f  is methyl, and R h  is benzyl or tert-butyl.  
 
     
     
       14. The compound of  claim 13 , wherein m is 1. 
     
     
       15. The compound of  claim 13 , wherein X is sulfonyl. 
     
     
       16. The compound of  claim 13 , wherein R W  is C 1-4  alkyl, C 4-7  cycloalkyl, or benzyl. 
     
     
       17. A compound having Formula I: 
                 
 
       or pharmaceutically acceptable salts thereof; wherein
 Q is naphth-1-yl, naphth-2-yl, 5-dimethylaminonaphth-1-yl, 6-chloronaphth-2-yl, 6-bromonaphth- 2-yl, benzyl, 2-nitrobenzyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-(n-propyl)phenyl, 4-(t-butyl)phenyl, 4-(t-amyl)phenyl, 4-methoxyphenyl, 4-iodophenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-methylphenyl, 4-ethylphenyl, 3,4-dimethoxyphenyl, or 2-phenylethenyl;  
 X is methylene, carbonyl, or sulfonyl;  
 R 1  is hydrogen or C 1-3  alkyl;  
 n is 1;  
 m is 1-4;  
 R 2  is hydrogen or C 1-3  alkyl;  
 R 3  is hydrogen or C 1-3  alkyl; and  
 R 4 , R 5  and R 6  are independently hydrogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, cyano or —CO 2 R W , R W  is C 1-4  alkyl, C 4-7  cycloalkyl, benzyl, 
                 
 
 R d , R e  and R g  are each hydrogen, R f  is methyl, and R h  is benzyl or tert-butyl.  
 
     
     
       18. The compound of  claim 17 , wherein m is 1 or 2. 
     
     
       19. The compound of  claim 17 , wherein m is 1. 
     
     
       20. A pharmaceutical composition comprising a compound of  claim 1 ; and a pharmaceutically acceptable carrier or diluent. 
     
     
       21. A method of treating a factor Xa mediated condition in a mammal, comprising administering to a mammal in need of said treatment a therapeutically or prophylactically effective amount of a compound of  claim 1 . 
     
     
       22. A method of treating thrombosis, ischemia, stroke, restenosis or inflammation comprising administering to a mammal in need of said treatment a therapeutically or prophylactically effective amount of a compound of  claim 1 . 
     
     
       23. A method of inhibiting coagulation on or in a medical device, comprising contacting, embedding, or linking a compound of  claim 1  to a medical device. 
     
     
       24. A method of making a compound of  claim 1 , comprising:
 coupling or condensing a compound of Formula II: 
                 
 
 
       or a salt thereof, where R 4 , R 5  and R 6  are as defined as in  claim 1  or optionally protected, and m is 1-4, with a compound of Formula III: 
                 
 
       where R 51  is H or Q-X.